Genetic susceptibility plays an important role in the development of type 2 diabetes mellitus. During the previous funding period, we identified and examined a panel of 112 large families in which type 2 diabetes was diagnosed at a young (43 families) or middle (69 families) age and was transmitted through three generations (1578 individuals including 810 diabetics) an apparently autosomal dominant pattern of inheritance. In these families, we found strong linkage between type 2 diabetes and a 0.3-1.0 Mb region on chromosome 20q. This region harbors a gene that accounts for typical insulin resistant diabetes in about one third of our families with onset in middle-age. In this renewal application, we propose to identify the putative susceptibility gene for type 2 diabetes located on the long arm of chromosome 20. Once cloned, the function of this gene will be characterized at the level of the cell, tissue, organism and population. Also, through a genome- wide scan and positional candidate gene approach, we will search for additional, highly penetrant susceptibility genes for type 2 diabetes in an expanded panel of highly informative families. All aspects of our research will be facilitated by the continuing refinement of Human Genome Project data. The probability of identifying a gene for type 2 diabetes on chromosome 20q is very high. This gene could be the first to account for a significant proportion of typical type 2 diabetes and, as such, it will provide insight to a pathway underlying the development of typical insulin-resistant diabetes. The innovation of the proposed research is the collection of families with "Mendelian" segregation of type 2 diabetes. Given past successes in identifying regions of importance for Mendelian disorders, we expect that our strategy based on families having an apparently autosomal dominant mode of inheritance will be highly productive in identifying susceptibility genes for type 2 diabetes, beyond that on chromosome 20q.